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Mar. Drugs 2017, 15(10), 320; doi:10.3390/md15100320

A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells

1
Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
2
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
*
Author to whom correspondence should be addressed.
Received: 26 September 2017 / Revised: 12 October 2017 / Accepted: 16 October 2017 / Published: 20 October 2017
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Abstract

Neopeltolide, an antiproliferative marine macrolide, is known to specifically inhibit complex III of the mitochondrial electron transport chain (mETC). However, details of the biological mode-of-action(s) remain largely unknown. This work demonstrates potent cytotoxic activity of synthetic neopeltolide analogue, 8,9-dehydroneopeltolide (8,9-DNP), against starved human pancreatic adenocarcinoma PANC-1 cells and human non-small cell lung adenocarcinoma A549 cells. 8,9-DNP induced rapid dissipation of the mitochondrial membrane potential and depletion of intracellular ATP level in nutrient-deprived medium. Meanwhile, in spite of mTOR inhibition under starvation conditions, impairment of cytoprotective autophagy was observed as the lipidation of LC3-I to form LC3-II and the degradation of p62 were suppressed. Consequently, cells were severely deprived of energy sources and underwent necrotic cell death. The autophagic flux inhibited by 8,9-DNP could be restored by glucose, and this eventually rescued cells from necrotic death. Thus, 8,9-DNP is a potent anti-austerity agent that impairs mitochondrial ATP synthesis and cytoprotective autophagy in starved tumor cells. View Full-Text
Keywords: macrolide; cytotoxicity; necrosis; mitochondrial inhibitor; anti-austerity; autophagy; cellular energy macrolide; cytotoxicity; necrosis; mitochondrial inhibitor; anti-austerity; autophagy; cellular energy
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Fuwa, H.; Sato, M. A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells. Mar. Drugs 2017, 15, 320.

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